Method for treating intraocular hypertension

ABSTRACT

Intraocular hypertensive diseases such as glaucoma are treated with compounds represented by formula I ##STR1## or a pharmaceutically acceptable acid addition salt thereof, wherein 
     R 1  is alkyl of two to four carbon atoms; and 
     R 2  is alkyl of three or four carbon atoms; or 
     R 1  and R 2  taken together with N form ##STR2##  wherein n is 0, 1, or 2 and R 5  and R 6  are each independently lower alkyl or hydro; 
     R 3  is hydro or hydroxy; 
     R 4  is hydro, lower alkyl, amino, or lower alkylamino.

RELATED U.S. APPLICATION DATA

This application is a divisional of U.S. application Ser. No. 722,038filed Apr. 11, 1985 (now U.S. Pat. No. 4,629,730 issued Dec. 16, 1986)to which earlier application Applicants claim priority under 35 USC 517120.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a method for treating intraocular hypertensivediseases such as glaucoma by direct administration of dialkyl orcycloalkyl aminoethylaniline derivatives or pharmaceutically acceptableacid addition salts of the invention. The invention also relates to apharmaceutically acceptable composition containing an effective amountof at least one of the compounds in combination with a suitableexcipient, the composition being useful for the treatment of intraocularhypertensive diseases such as glaucoma in mammals. The invention alsorelates to the use of a compound of the invention to prepare apharmaceutical composition useful for the treatment of intraocularhypertensive diseases such as glaucoma in mammals.

2. Related Disclosures

Certain alkyl and dialkyl aminoethylanilines are known. See, forexample, U.S. Pat. Nos. 4,287,211, 4,404,222, 3,803,230, and 3,689,524and German Pat. No. 2,612,354. A novel use for a class of dialkyl- andcycloalkyl-aminoethylaniline derivatives has now been discovered.

SUMMARY OF THE INVENTION

The first aspect of this invention is the method of treatment ofintraocular hypertensive diseases such as glaucoma with a compoundselected from the group of compounds represented by formula I ##STR3##or a pharmaceutically acceptable acid addition salt thereof, wherein

R₁ is alkyl of two to four carbon atoms; and

R₂ is alkyl of three or four carbon atoms; or

R₁ and R₂ taken together form ##STR4## wherein n is 0, 1, or 2 and R₅and R₆ are each independently lower alkyl or hydro;

R₃ is hydro or hydroxy; and

R₄ is hydro, lower alkyl, amino, or lower alklamino.

Another aspect of the invention is a composition useful in the treatmentof intraocular hypertensive diseases such as glaucoma in mammals whichcomposition comprises an effective amount of at least one compoundchosen from those represented by formula I above or a pharmaceuticallyacceptable acid addition salt thereof and a pharmaceutically suitableexcipient.

Another aspect of the invention is the use of a compound of theinvention in a pharmaceutical composition suitable for the treatment ofan intraocular hypertensive disease.

DETAILED DESCRIPTION AND PREFERRED EMBODIMENTS

The broadest aspect of the present invention is the method of treatingan intraocular hypertensive disease comprising directly administering toa mammal in need thereof a compound selected from the group of compoundsrepresented by the formula ##STR5## or a pharmaceutically acceptableacid addition salt thereof, wherein

R₁ is alkyl of two to four carbon atoms; and

R₂ is alkyl of three or four carbon atoms; or

R₁ and R₂ taken together with N form ##STR6## wherein n is 0, 1, or 2and R₅ and R₆ are each independently lower alkyl or hydro;

R₃ is hydro or hydroxy; and

R₄ is hydro, lower alkyl, amino, or lower alkylamino.

One preferred subgenus of compounds of formula I is that wherein R₃ ishydro, particularly where R₄ is amino. A preferred compound is thatwherein R₁ and R₂ are each n-propyl.

Another preferred subgenus of compounds of formula I is that wherein R₁and R₂ taken together with N form ##STR7## where n is 1 and R₅ and R₆are methyl. A particularly preferred compound is that wherein R₃ ishydro and R₄ is amino.

Another aspect of the invention is the use of a compound of formula I ina pharmaceutical composition useful for the treatment of intraocularhypertensive diseases such as glaucoma in mammals.

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term "lower alkyl" refers to a straight or branched chain monovalentsubstituent consisting solely of carbon and hydro, containing nounsaturation and having from one to four carbon atoms. Examples of loweralkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,s-butyl and t-butyl.

The term "pharmaceutically acceptable acid addition salts" refers tosalts of the subject compounds which possess the desired pharmacologicalactivity and which are neither biologically nor otherwise undesirable.These salts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid; ororganic acids such as acetic acid, propionic acid, glycolic acid,pyruvic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid,mandelic acid, methanesulfonic acid, ethanesulfonic acid,p-toluenesulfonic acid and the like.

The term "opthamologically acceptable" means suitable for use in theeye. I.e., an opthamologically acceptable carrier does not causeirritation when administered directly to the eye.

The term "direct administration" means administration directly to theeye of the subject, and excludes general systemic administration. Directadministration includes, without limitation, topical application ofaqueous solutions and ointments, administration of controlled releasedevices, and subconjunctival injection.

The term "treatment" as used herein covers any treatment of anintraocular hypertensive disease in a mammal, particularly a human, andincludes:

(i) preventing the disease from occurring in a subject which may bepredisposed to the disease but has not yet been diagnosed as having it;

(ii) inhibiting the disease, i.e., arresting its development; or

(iii) relieving the disease, i.e., causing regression of the disease.

Certain compounds of formula I wherein R₁ and R₂ together with N form##STR8## where R₅ and R₆ are not identical may have geometric (cis andtrans) isomers. The wavy lines are used to indicate that either the cisisomer, trans isomer, or a mixture may be used. The isomers may beseparated by various methods, for example selective crystallization andcolumn chromatography. Alternatively, the free base (e.g.,3,5-dimethylpiperidine) may be resolved before it is incorporated intothe compound of the invention. (The invention includes all geometricisomers of any asymmetric compound of formula I, as well as mixturesthereof.)

ADMINISTRATION AND FORMULATION

Ophthalmic preparations are sterile products for either topicalapplication to the eyes or instillation into the space (cul-de-sac)between the eyeball and the eyelids. Presently available ophthalmicpreparations include solutions, suspensions, ointments, and controlledrelease preparations. Presently available treatments of eye diseasesinclude topically applied opthalmic drops, solutions, suspensions orointment or their subconjunctival injection.

The composition of this invention comprises a compound of formula I (asdefined herein) or a salt thereof in admixture with anophthalmologically acceptable excipient.

An excipient is ophthalmologically acceptable if it is non-irritating tothe eye and non-toxic at effective levels.

The ophthalmic composition may be aqueous or non-aqueous, and it may bein the form of a solution, suspension, gel, ointment, slow releasepolymer, or other. The amount of active ingredient will vary with theparticular formulation and disease state but generally will be between0.001-10% wt/vol of active ingredient per individual application dose,preferably between 0.005-7% wt/vol.

Pharmaceutical ophthalmic compositions are typically provided assterilized aqueous solutions (i.e. eyedrops) containing 0.001% to 10%wt/vol.; most preferably 0.005% to 1% of the active ingredient, alongwith a suitable buffer, stabilizer, and preservative. The totalconcentration of solutes should be such that, if possible, the resultingsolution is isotonic with the lacrimal fluid (though this is notabsolutely necessary) and has an equivalent pH (in the range of pH 6-8).Typical preservatives/sterilants are phenylmercuric acetate, thimerosal,chlorobutanol, and benzalkonium chloride. Typical buffer systems andsalts are based on, for example, citrate, borate or phosphate; suitablestabilizers include glycerin and polysorbate 80. The aqueous solutionsare formulated simply by dissolving the components in a suitablequantity of water, adjusting the pH to about 6.8-8.0, making a finalvolume adjustment with additional water, and sterilizing the preparationusing methods known to those skilled in the art.

The dosage level of the resulting composition will, of course, depend onthe concentration of the drops, the condition of the subject and theindividual magnitude of responses to treatment. However, typical dosageranges might be about 2-10 drops of 0.1% solution of active ingredientonce to three times per day.

Most ophthalmic solutions and suspensions contain an aqueous rather thanan oily vehicle. Ophthalmic ointments usually contain a whitepetrolatum-mineral oil base, often including anhydrous lanolin, whilesome have a polyethylene-gelled mineral oil base.

Solutions are the most commonly used type of preparation for the localmedication of eyes. They are easily instilled and rarely cause adversereactions. The vehicle should not interfere with vision and should notinterfere with regeneration of the corneal epithelium.

Suspensions have the advantage of more extended action and thedisadvantage that it is difficult to avoid the presence of a fewparticles which are large enough to cause irritation.

Eye ointments are sterile preparations for application to theconjunctival sac or lid margin. They have advantages of more prolongedcontact and effect, minimal irritation on initial installation, slowermovement into lacrimal ducts, greater storage stability, and lesslikelihood of contamination problems. Their disadvantages are that theyproduce a film over the eye thereby blurring vision, and may interferewith the firm attachment of new corneal epithelial cells to their normalbase. Ointments affect the outside and edges of the eyelids, theconjunctiva, the cornea, and the iris, depending on their ability topenetrate the outer covering of the eyeball.

Ophthalmic ointments comprising active ingredients can be used on theoutside and edges of the eyelids, the conjunctiva, and the cornea. Mostophthalmic ointments are prepared with a base of white or yellowpetrolatum and mineral oil, often with added anhydrous lanolin.Whichever base is selected, it must be nonirritating to the eye, permitdiffusion of the drug throughout the secretions bathing the eye, andretain the activity of the medicament for a reasonable period of timeunder proper storage conditions.

Compounds of this invention may also be administered by othernonsystemic modes. Ophthalmic packs may be used to give prolongedcontact of the solution with the eye. For example, a cotton pledgetsaturated with an ophthalmologically suitable solution of a compound ofthis invention may be inserted into the superior or inferior fornix.Medicated controlled-release ophthalmic disks may produce effects bothmore intense and prolonged than solutions. See, e.g., U.S. Pat. No.4,190,642, incorporated herein by reference, which discloses acontrolled-release device for administering compounds to the eye, whichmay be useful in the practice of this invention.

The compounds of the invention may also be administered by the way ofiontophoresis. This procedure keeps the solution in contact with thecornea in an eyecup bearing an electrode. Diffusion of the drug iseffected by difference of electrical potential. Remington'sPharmaceutical Sciences, 15th Ed., 1489-1504, (1975).

PREPARATION OF THE INVENTION

Compounds of formula I are prepared by the reaction sequence shownbelow. ##STR9## wherein R₁, R₂, R₃, and R₄ are as defined above in thebroadest aspect of the invention, Ts is tosyl (p-toluenesulfonyl), A isbenzyloxy (BzO) or hydro, BzCl is benzyl chloride, and R is lower alkyl.

When compounds in which R₃ is hydro are desired, steps (1) and (7) arenot necessary and are omitted; in such cases step (6a, b, c, or d) isthe final step.

For compounds in which R₃ is hydroxy, 4-hydroxy-3-nitrophenylacetic acid(II), available, e.g., from Aldrich Chemical Co., is first converted tothe methyl ester, then reacted with an equimolar amount of benzylchloride, also available, e.g., from Aldrich Chemical Co., using theWilliamson Ether Synthesis to yield a hydroxy-protected methyl4-benzyloxy-3-nitrophenylacetate (III, A=BzO). The reaction is usuallyperformed using potassium carbonate in refluxing acetonitrile orethanol. (Step 1).

The protected nitrophenylacetic acid ester (III, A=BzO) is then reduced,using borane-methyl sulfide in a tetrahydrofuran (THF) solution at roomtemperature. After acidification with HCl in methanol, the solution isevaporated, and the product 4-benzyloxy-3-nitrophenylethanol (IV, A=BzO)extracted from aqueous sodium carbonate with diethyl ether (Et₂ O).Similarly, compounds in which A=H may be prepared by the same method,substituting 3-nitrophenylacetic acid (III, A=H) for methyl4-benzyloxy-3-nitrophenylacetate. 3-Nitrophenylacetic acid is availablecommecially from e.g. Aldrich Chemical Co. (Step 2.)

The 4-benzyloxy-3-nitrophenylethanol (IV, A=BzO) is then reacted with amolar excess of p-toluenesulfonyl chloride in pyridine at 0° C. toproduce a 4-benzyloxy-3-nitrophenylethyl tosylate (V, A=BzO). Thetosylate (V, A=BzO) is extracted using ethyl acetate. Similarly,compounds in which A=H may be prepared by the same method, substituting3-nitrophenylethanol (IV, A=H) for 4-benzyloxy-3-nitrophenylethanol.(Step 3.)

The tosylate (V, A=BzO) is reacted with an equimolar amount of thedesired dialkyl amine or cycloalkyl amine in dimethylformamide (DMF) at65° C. to produce a 2-benzyloxy-5-dialkyl or cycloalkylaminoethylnitrobenzene (VI, A=BzO). Similarly, compounds in which A₃₂ Hmay be prepared by the same method, substituting 3-nitrophenylethyltosylate (V, A=H) for 4-benzyloxy-3-nitrophenylethyl tosylate. Dialkyland cycloalkyl amines may be obtained from commercial sources, e.g.,Aldrich Chemical Co., or may be made by methods known in the art (Step4.)

The 2-benzyloxy-5-dialkyl or cycloalkyl aminoethylnitrobenzene (VI,A=BzO) is then reduced to a 2-benzyloxy-5-dialkyl or cycloalkylaminoethylaniline derivative (VII, A=BzO) with hydrazine and Raneynickel in refluxing ethanol at ambient pressure with an equimolar amountof hydrogen, using the general method known for other unrelatedcompounds. See, e.g., Introduction to Organic Chemistry, by AndrewStreitwieser, Jr., and Clayton H. Heathcock, Ch. 32, p. 961 (1976).Similarly, compounds in which A=H may be prepared by the same method,substituting 3-dialkyl or cycloalkyl aminoethylnitrobenzene (VI, A=H)for 2-benzyloxy-5-dialkyl or cycloalkyl aminoethylnitrobenzene. (Step5.)

The sequence is completed by reacting the aniline derivative formylderivative, carboxylic acid derivative, isocyanate, or alkylisocyanate.

If a formamido derivative (VIIIa, A=H or BzO) is desired, the novelaniline derivative (VII, A=H or BzO) is reacted at 0° C. with anequimolar amount of an appropriate reactive formyl derivative (e.g.,formic acetic anhydride, which may be generated in situ from sodiumformate and acetyl chloride, which are commercially available) in anappropriate aprotic base. (Step 6a.)

To produce a compound in which R₄ is lower alkyl (VIIIb, A=H or BzO),the aniline derivative (VII, A=H or BzO) is reacted at 25° C. with anequimolar amount of an appropriate reactive carboxylic acid derivative,especially an acyl halide, in an appropriate aprotic base. Carboxylicacid chlorides are available commercially, or may be prepared fromcommercially available carboxylic acids by methods known in the art.(Step 6b.)

To produce a ureidobenzene derivative (VIIIc, A=H or BzO), the anilinederivative (VII, A=H or BzO) is reacted at 25° C. with an equimolaramount of an appropriate cyanate salt, e.g., potassium cyanate, in anacidic medium. (Step 6c.)

To produce an alkyl ureidobenzene derivative (VIIId, A=H or BzO), theaniline derivative (VII, A=H or BzO) is reacted at 25° C. with anequimolar amount of an appropriate alkyl isocyanate, using the generalmethod known in the art for unrelated compounds. See, e.g., Introductionto Organic Chemistry, Streitwieser & Heathcock, Ch. 27, p. 801. Alkylisocyanates may be obtained commercially, or may be produced by reactingthe appropriate alkyl halide with a reactive cyanate salt. (Step 6d.)

In compounds wherein R₃ is hydro, Step 6a, b, c, or d produces thecompound of formula I directly. Where R₃ is hydroxy, it is necessary toremove the benzyloxy protecting group. This may be accomplished by themethod described in Catalytic Hydrogenation in Organic Synthesis:Procedures and Commentary, M. Freifelder, (Wiley, 1978), p. 109, e.g.,by catalytic hydrogenolysis of the penultimate compound (VIIIa-d) usingpalladium on carbon in methanol at ambient temperature and a pressure of2 atmospheres, affording the compound of the invention (I).

In summary, compound of formula I are prepared by the following methods:

Compounds of formula I in which R₃ is H are prepared by reacting acompound of formula VII (where A=H) with an appropriate reactive formylderivative, carboxylic acid derivative, isocyanate salt, oralkylisocyanate, to produce the corresponding formanilide derivative,alkanylanilide derivative, ureidobenzene derivative, or alkylureaderivative. These reactions may be performed at atmospheric pressure,and at temperatures between the freezing and boiling points of thesolvents employed, preferably between about -5° C. and about 110° C.,and most preferably at about 25° C.

Compounds of formula I in which R₃ is OH are prepared by performing thesame procedure using a compound of formula VII (where A=BzO), followedby removal of the protecting benzyloxy group, e.g., by catalytichydrogenolysis with H₂ over palladium on carbon at about 60° C. andpressure of about two atmospheres.

Pharmaceutically acceptable acid addition salts of the compounds offormula I are prepared by reacting a free base of formula I with anappropriate acid. Free bases of formula I are prepared by reacting anacid addition salt of a compound of formula I with an appropriate base.

The following specific description is given to enable those skilled inthe art to more clearly understand and practice the invention. It shouldnot be considered as a limitation upon the scope of the invention, butmerely as being illustrative and representative thereof.

PREPARATION 1 (Preparation of Compounds of Formula III Wherein A isBenzyloxy) (Step 1)

The carboxy function of 4-hydroxy-3-nitrophenylacetic acid (II) is firstprotected by forming the methyl ester using HCl in methanol, theprocedure for which is known in the art. Then, 10.5 g methyl4-hydroxy-3-nitrophenylacetate and 10 g benzyl chloride are reacted with5 g potassium carbonate in ethanol. The product is extracted with ether.

PREPARATION 2 (Preparation of Compounds of Formula IV Wherein A isHydrogen or Benzyloxy) (Step 2)

(A) 40 g of 3-nitrophenylacetic acid was added to a solution of 26 ml of10M borane-methyl sulfide in 200 ml of THF, and the mixture was stirredat 25° C. for 3 hr. The solution was then acidified with HCl inmethanol, followed by evaporation of the solvent. The product3-nitrophenylethanol (IV, A=H) was partitioned between diethyl ether(Et₂ O) and aqueous sodium carbonate, and the Et₂ O layer dried oversodium sulfate. Evaporation of the Et₂ O afforded 34.8 g of3-nitrophenylethanol (IV, A=H) as an oil.

(B) Similarly, proceeding as in Part A above, but substituting methyl4-benzyloxy-3-nitrophenylacetate for 3-nitrophenylacetic acid, thecompound 4-benzyloxy-3-nitrophenylethanol (IV, A=BzO) is produced.

PREPARATION 3 (Preparation of Compounds of Formula V) (Step 3)

(A) 34.6 g of 3-nitrophenylethanol (IV, A=H) was added to 41 g ofp-toluenesulfonyl chloride in 200 ml of pyridine at 0° C. and allowed tostand for 24 hr. Water was added, and the mixture extracted with ethylacetate. The ethyl acetate extract was washed with 5% HCl, water, andbrine, dried over Na₂ SO₄, and evaporated to a residue. The residue wasrecrystallized from Et₂ O to afford 34 g of 3-nitrophenylethyltosylate(V, A=H).

(B) Similarly, proceeding as in Part A above, but substituting4-benzyloxy-3-nitrophenylethanol for 3-nitrophenylethanol, the compound4-benzyloxy-3-nitrophenylethyltosylate (V, A=BzO) is produced.

PREPARATION 4 (Preparation of Compounds of Formula VI) (Step 4)

(A) A mixture of 18.8 g of 3-nitrophenylethyl-2-tosylate and 25 ml ofdi-n-propylamine in 100 ml of DMF was stirred at 65° C. for 12 hr. Thesolution was diluted with water and acidified with HCl. The mixture wasthen washed with Et₂ O, basified with NH₄ OH, and extracted with ethylacetate. Evaporation of the solvent (after drying over Na₂ SO₄) produced10.1 g of 3-(2-N,N-di-n-propylaminoethyl)nitrobenzene (VI, A=H).

(B) Similarly, proceeding as above, substituting the appropriatedialkylamine or cycloalkylamine for di-n-propylamine, the followingcompounds (VI, A=H) are prepared:

3-(2-N,N-ethyl-n-propylaminoethyl)nitrobenzene;

3-(2-N,N-ethyl-i-propylaminoethyl)nitrobenzene;

3-(2-N,N-ethyl-n-butylaminoethyl)nitrobenzene;

3-(2-N,N-ethyl-s-butylaminoethyl)nitrobenzene;

3-(2-N,N-ethyl-t-butylaminoethyl)nitrobenzene;

3-(2-N,N-n-propyl-n-butylaminoethyl)nitrobenzene;

3-(2-N,N-n-propyl-s-butylaminoethyl)nitrobenzene;

3-(2-N,N-n-propyl-t-butylaminoethyl)nitrobenzene;

3-(2-N,N-diisopropylaminoethyl)nitrobenzene;

3-(2-N,N-i-propyl-n-butylaminoethyl)nitrobenzene;

3-(2-N,N-i-propyl-s-butylaminoethyl)nitrobenzene;

3-(2-N,N-di-n-butylaminoethyl)nitrobenzene;

3-[2-(1-piperidyl)ethyl]nitrobenzene;

3-[2-(3,5-dimethyl-1-piperidyl)ethyl]nitrobenzene;

3-[2-(1-pyrrolidyl)ethyl]nitrobenzene;

3-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]nitrobenzene; and

3-[2-(1-azacycloheptyl)ethyl]nitrobenzene.

(C) Similarly, proceeding as in Part A and Part B above, butsubstituting 4-benzyloxy-3-nitrophenylethyltosylate for3-nitrophenylethyltosylate, the following compounds (VI, A=BzO) areproduced:

2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)nitrobenzene;

2-benzyloxy-5-(2-N,N-ethyl-n-propylaminoethyl)nitrobenzene;

2-benzyloxy-5-(2-N,N-ethyl-i-propylaminoethyl)nitrobenzene;

2-benzyloxy-5-(2-N,N-ethyl-n-butylaminoethyl)nitrobenzene;

2-benzyloxy-5-(2-N,N-ethyl-s-butylaminoethyl)nitrobenzene;

2-benzyloxy-5-(2-N,N-ethyl-t-butylaminoethyl)nitrobenzene;

2-benzyloxy-5-(2-N,N-n-propyl-n-butylaminoethyl)nitrobenzene;

2-benzyloxy-5-(2-N,N-n-propyl-s-butylaminoethyl)nitrobenzene;

2-benzyloxy-5-(2-N,N-n-propyl-t-butylaminoethyl)nitrobenzene;

2-benzyloxy-5-(2-N,N-diisopropylaminoethyl)nitrobenzene;

2-benzyloxy-5-(2-N,N-i-propyl-n-butylaminoethyl)nitrobenzene;

2-benzyloxy-5-(2-N,N-i-propyl-s-butylaminoethyl)nitrobenzene;

2-benzyloxy-5-(2-N,N-di-n-butylaminoethyl)nitrobenzene;

2-benzyloxy-5-[2-(1-piperidyl)ethyl]nitrobenzene;

2-benzyloxy-5-[2-(3,5-dimethyl-1-piperidyl)ethyl]nitrobenzene;

2-benzyloxy-5-[2-(1-pyrrolidyl)ethyl]nitrobenzene;

2-benzyloxy-5-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]nitrobenzene; and

2-benzyloxy-5-[2-(1-azacycloheptyl)ethyl]nitrobenzene.

PREPARATION 5 (Preparation of Compounds of Formula VII, NovelIntermediates of the Invention) (Step 5)

(A) To 10.1 g of 3-(2-N,N-di-n-propylaminoethyl)nitrobenzene (VI) in 200ml of ethanol was added 1.0 g of Raney nickel and the solution heated toreflux. A solution of 10 ml of hydrazine hydrate in ethanol was slowlyadded. After filtration and evaporation, the mixture yielded 6.8 g of3-(2-N,N-di-n-propylaminoethyl)aniline (VII, A=H) as an oil.

(B) Similarly, proceeding as in Part A above, but substituting thecompounds made in Preparation 4(B) above for3-(2-N,N-di-n-propylaminoethyl)nitrobenzene, the following compounds areprepared:

3-(2-N,N-ethyl-n-propylaminoethyl)aniline;

3-(2-N,N-ethyl-i-propylaminoethyl)aniline;

3-(2-N,N-ethyl-n-butylaminoethyl)aniline;

3-(2-N,N-ethyl-s-butylaminoethyl)aniline;

3-(2-N,N-ethyl-t-butylaminoethyl)aniline;

3-(2-N,N-n-propyl-n-butylaminoethyl)aniline;

3-(2-N,N-n-propyl-s-butylaminoethyl)aniline;

3-(2-N,N-n-propyl-t-butylaminoethyl)aniline;

3-(2-N,N-diisopropylaminoethyl)aniline;

3-(2-N,N-i-propyl-n-butylaminoethyl)aniline;

3-(2-N,N-i-propyl-s-butylaminoethyl)aniline;

3-(2-N,N-di-n-butylaminoethyl)aniline;

3-[2-(1-piperidyl)ethyl]aniline;

3-[2-(3,5-dimethyl-1-piperidyl)ethyl]aniline;

3-[2-(1-pyrrolidyl)ethyl]aniline;

3-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]aniline; and

3-[2-(1-azacycloheptyl)ethyl]aniline.

(C) Similarly, proceeding as in Part A and Part B above, butsubstituting the compounds prepared in Preparation 4(C) above for3-(2-N,N-di-n-propylaminoethyl)nitrobenzene, the following compounds(VII, A=BzO) are prepared:

2-benzyloxy-5-(2-N,N-ethyl-n-propylaminoethyl)aniline;

2-benzyloxy-5-(2-N,N-ethyl-i-propylaminoethyl)aniline;

2-benzyloxy-5-(2-N,N-ethyl-n-butylaminoethyl)aniline;

2-benzyloxy-5-(2-N,N-ethyl-s-butylaminoethyl)aniline;

2-benzyloxy-5-(2-N,N-ethyl-t-butylaminoethyl)aniline;

2-benzyloxy-5-(2-N,N-n-propyl-n-butylaminoethyl)aniline;

2-benzyloxy-5-(2-N,N-n-propyl-s-butylaminoethyl)aniline;

2-benzyloxy-5-(2-N,N-n-propyl-t-butylaminoethyl)aniline;

2-benzyloxy-5-(2-N,N-diisopropylaminoethyl)aniline;

2-benzyloxy-5-(2-N,N-i-propyl-n-butylaminoethyl)aniline;

2-benzyloxy-5-(2-N,N-i-propyl-s-butylaminoethyl)aniline;

2-benzyloxy-5-(2-N,N-di-n-butylaminoethyl)aniline;

2-benzyloxy-5-[2-(1-piperidyl)ethyl]aniline;

2-benzyloxy-5-[2-(3,5-dimethyl-1-piperidyl)ethyl]aniline;

2-benzyloxy-5-[2-(1-pyrrolidyl)ethyl]aniline;

2-benzyloxy-5-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]aniline; and

2-benzyloxy-5-[2-(1-azacycloheptyl)ethyl]aniline.

EXAMPLE 1 (Preparation of Compounds of Formula VIIIa) (Step 6a)

(A) 3.4 g of sodium formate is added to 3.6 ml of acetyl chloride in 20ml THF at 0° C. and allowed to stand for 24 hr to form formic aceticanhydride. To this solution is added 10 g of3-(2-N,N-di-n-propylaminoethyl)aniline in 50 ml of pyridine. Thesolution is allowed to stand at 0° C. for 12 hr, and is then added towater and extracted with CH₂ Cl₂. The solvent is evaporated, and theresidue is purified by silica gel chromatography to afford3-(2-N,N-di-n-propylaminoethyl)formanilide (VIIIa, A=H).

(B) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Preparation 5(B) above for3-(2-N,N-di-n-propylaminoethyl)aniline, the following compounds (VIIIa,A=H) are prepared:

3-(2-N,N-ethyl-i-propylaminoethyl)formanilide;

3-(2-N,N-ethyl-n-butylaminoethyl)formanilide;

3-(2-N,N-ethyl-s-butylaminoethyl)formanilide;

3-(2-N,N-ethyl-t-butylaminoethyl)formanilide;

3-(2-N,N-n-propyl-n-butylaminoethyl)formanilide;

3-(2-N,N-n-propyl-s-butylaminoethyl)formanilide;

3-(2-N,N-n-propyl-t-butylaminoethyl)formanilide;

3-(2-N,N-diisopropylaminoethyl)formanilide;

3-(2-N,N-i-propyl-n-butylaminoethyl)formanilide;

3-(2-N,N-i-propyl-s-butylaminoethyl)formanilide;

3-(2-N,N-di-n-butylaminoethyl)formanilide;

3-[2-(1-piperidyl)ethyl]formanilide;

3-[2-(3,5-dimethyl-1-piperidyl)ethyl]formanilide;

3-[2-(1-pyrrolidyl)ethyl]formanilide;

3-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]formanilide; and

3-[2-(1-azacycloheptyl)ethyl]formanilide.

(C) Similarly, proceeding as in Part A and Part B above, butsubstituting the compounds prepared in Preparation 5(C) for3-(2-N,N-di-n-propylaminoethyl)aniline, the following compounds (VIIIa,A=BzO) are prepared:

2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)formanilide;

2-benzyloxy-5-(2-N,N-ethyl-n-propylaminoethyl)formanilide;

2-benzyloxy-5-(2-N,N-ethyl-i-propylaminoethyl)formanilide;

2-benzyloxy-5-(2-N,N-ethyl-n-butylaminoethyl)formanilide;

2-benzyloxy-5-(2-N,N-ethyl-s-butylaminoethyl)formanilide;

2-benzyloxy-5-(2-N,N-ethyl-t-butylaminoethyl)formanilide;

2-benzyloxy-5-(2-N,N-n-propyl-n-butylaminoethyl)formanilide;

2-benzyloxy-5-(2-N,N-n-propyl-s-butylaminoethyl)formanilide;

2-benzyloxy- 5-(2-N,N-n-propyl-t-butylaminoethyl)formanilide;

2-benzyloxy-5-(2-N,N-diisopropylaminoethyl)formanilide;

2-benzyloxy-5-(2-N,N-i-propyl-n-butylaminoethyl)formanilide;

2-benzyloxy-5-(2-N,N-i-propyl-s-butylaminoethyl)formanilide;

2-benzyloxy-5-(2-N,N-di-n-butylaminoethyl)formanilide;

2-benzyloxy-5-[2-(1-piperidyl)ethyl]formanilide;

2-benzyloxy-5-[2-(3,5-dimethyl-1-piperidyl)ethyl]formanilide;

2-benzyloxy-5-[2-(1-pyrrolidyl)ethyl]formanilide;

2-benzyloxy-5-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]formanilide; and

2-benzyloxy-5-[2-(1-azacycloheptyl)ethyl]formanilide.

EXAMPLE 2 (Preparation of Compounds of Formula VIIIb) (Step 6b)

(A) 3.5 g of 3-(2-N,N-di-n-propylaminoethyl)aniline in 20 ml of pyridineis treated with 1 ml of acetyl chloride at 0° C. The solution is addedto water and extracted with CH₂ Cl₂. The solvent is evaporated and theproduct 3-(2-N,N-di-n-propylaminoethyl)acetanilide (VIIIb, A=H) ispurified by silica gel chromatography (HBr salt m.p. 212°-213° C.).

(B) Similarly, proceeding as in Part A above, but substituting propanoylchloride or butanoyl chloride for acetyl chloride, the followingcompounds are prepared:

3-(2-N,N-di-n-propylaminoethyl)propionanilide;

3-(2-N,N-di-n-propylaminoethyl)butyranilide.

(C) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Preparation 5(B) above for3-(2-N,N-di-n-propylaminoethyl)aniline, the following compounds (VIIIb,A=H) are prepared:

3-(2-N,N-ethyl-n-propylaminoethyl)acetanilide;

3-(2-N,N-ethyl-i-propylaminoethyl)acetanilide;

3-(2-N,N-ethyl-n-butylaminoethyl)acetanilide;

3-(2-N,N-ethyl-s-butylaminoethyl)acetanilide;

3-(2-N,N-ethyl-t-butylaminoethyl)acetanilide;

3-(2-N,N-n-propyl-n-butylaminoethyl)acetanilide;

3-(2-N,N-n-propyl-s-butylaminoethyl)acetanilide;

3-(2-N,N-n-propyl-t-butylaminoethyl)acetanilide;

3-(2-N,N-diisopropylaminoethyl)acetanilide;

3-(2-N,N-i-propyl-n-butylaminoethyl)acetanilide;

3-(2-N,N-i-propyl-s-butylaminoethyl)acetanilide;

3-(2-N,N-di-n-butylaminoethyl)acetanilide;

3-[2-(1-piperidyl)ethyl]acetanilide;

3-[2-(3,5-dimethyl-1-piperidyl)ethyl]acetanilide;

3-[2-(1-pyrrolidyl)ethyl]acetanilide;

3-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]acetanilide; and

3-[2-(1-azacycloheptyl)ethyl]acetanilide.

(D) Similarly, proceeding as in Parts A, B, and C above, butsubstituting the compounds made in Preparation 5(C) for3-(2-N,N-di-n-propylaminoethyl)aniline and propanoyl chloride orbutanoyl chloride for acetyl chloride, the corresponding propionanilideand butyranilide derivatives (VIIIb, A=H) are prepared.

(E) Similarly, proceeding as in Part A above, but substituting thecompounds made in Preparation 5(C) for3-(2-N,N-di-n-propylaminoethyl)aniline, the following compounds (VIIIb,A=BzO) are prepared:

2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N,N-ethyl-n-propylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N,N-ethyl-i-propylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N,N-ethyl-n-butylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N,N-ethyl-s-butylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N,N-ethyl-t-butylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N,N-n-propyl-n-butylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N,N-n-propyl-s-butylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N,N-n-propyl-t-butylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N,N-diisopropylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N,N-i-propyl-n-butylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N,N-i-propyl-s-butylaminoethyl)acetanilide;

2-benzyloxy-5-(2-N,N-di-n-butylaminoethyl)acetanilide;

2-benzyloxy-5-[2-(1-piperidyl)ethyl]acetanilide;

2-benzyloxy-5-[2-(3,5-dimethyl-1-piperidyl)ethyl]acetanilide;

2-benzyloxy-5-[2-(1-pyrrolidyl)ethyl]acetanilide;

2-benzyloxy-5-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]acetanilide; and

2-benzyloxy-5-[2-(1-azacycloheptyl)ethyl]acetanilide.

(F) Similarly, proceeding as in Parts B and E above, the corresponding2-benzyloxy-propionanilide and butyranilide derivatives (VIIIb, A=BzO)are prepared.

EXAMPLE 3 (Preparation of Compounds of Formula VIIIc) (Step 6c)

(A) A solution of 2.2 g of 3-(2-N,N-di-n-propylaminoethy)aniline in 10ml 2:1 water/acetic acid was treated with 1.5 g of potassium cyanate in5 ml of water. The mixture was then made basic with NH₄ OH and extractedwith CH₂ Cl₂. The CH₂ Cl₂ was evaporated, and the residue dissolved inmethanol. Then, 48% aqueous HBr or HCl was added until the solution wasacidic. The product, 3-(2-N,N-di-n-propylaminoethyl)ureidobenzene.HBr,(VIIIc, A=H) was precipitated from the solution with Et₂ O. The yieldwas 3.0 g, m.p. 186°-189° C.

(B) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Preparation 5(B) above for3-(2-N,N-di-n-propylaminoethyl)aniline, the following compounds (VIIIc,A=H) are prepared:

3-(2-N,N-ethyl-n-propylaminoethyl)ureidobenzene.HBr;

3-(2-N,N-ethyl-i-propylaminoethyl)ureidobenzene.HBr;

3-(2-N,N-ethyl-n-butylaminoethyl)ureidobenzene.HBr;

3-(2-N,N-ethyl-s-butylaminoethyl)ureidobenzene.HBr;

3-(2-N,N-ethyl-t-butylaminoethyl)ureidobenzene.HBr;

3-(2-N,N-n-propyl-n-butylaminoethyl)ureidobenzene.HCl, m.p. 194°-196°C.;

3-(2-N,N-n-propyl-s-butylaminoethyl)ureidobenzene.HBr;

3-(2-N,N-n-propyl-t-butylaminoethyl)ureidobenzene.HBr;

3-(2-N,N-diisopropylaminoethyl)ureidobenzene.HBr;

3-(2-N,N-i-propyl-n-butylaminoethyl)ureidobenzene.HBr;

3-(2-N,N-i-propyl-s-butylaminoethyl)ureidobenzene.HBr;

3-(2-N,N-di-n-butylaminoethyl)ureidobenzene.HCl, m.p. 200°-200.5° C.;

3-[2-(1-piperidyl)ethyl]ureidobenzene.HBr;

3-[2-(3,5-dimethyl-1-piperidyl)ethyl]ureidobenzene.HCl, m.p. 189°-191°C.;

3-[2-(1-pyrrolidyl)ethyl]ureidobenzene.HBr;

3-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]ureidobenzene.HBr; and

3-[2-(1-azacycloheptyl)ethyl]ureidobenzene.HBr.

(C) Similarly, proceeding as in Part A and Part B above, butsubstituting the compounds prepared in Preparation 5(C) for3-(2-N,N-di-n-propylaminoethyl)aniline, the following compounds (VIIIc,A=BzO) are produced:

2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-(2-N,N-ethyl-n-propylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-(2-N,N-ethyl-i-propylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-(2-N,N-ethyl-n-butylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-(2-N,N-ethyl-s-butylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-(2-N,N-ethyl-t-butylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-(2-N,N-n-propyl-n-butylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-(2-N,N-n-propyl-s-butylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-(2-N,N-n-propyl-t-butylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-(2-N,N-diisopropylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-(2-N,N-i-propyl-n-butylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-(2-N,N-i-propyl-s-butylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-(2-N,N-di-n-butylaminoethyl)ureidobenzene.HBr;

2-benzyloxy-5-[2-(1-piperidyl)ethyl]ureidobenzene.HBr;

2-benzyloxy-5-[2-(3,5-dimethyl-1-piperidyl)ethyl]ureidobenzene.HBr;

2-benzyloxy-5-[2-(1-pyrrolidyl)ethyl]ureidobenzene.HBr;

2-benzyloxy-5-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]ureidobenzene.HBr; and

2-benzyloxy-5-[2-(1-azacycloheptyl)ethyl]ureidobenzene.HBr.

EXAMPLE 4 (Preparation of Compounds of Formula VIIId) (Step 6d)

(A) A solution of 2.2 g of 3-(2-N,N-di-n-propylaminoethyl)aniline in 10ml of 2:1 water/acetic acid is treated with 1.1 g of methyl isocyanatein 5 ml of water. The mixture is made basic with NH₄ OH and extractedwith CH₂ Cl₂. The solvent is evaporated to afford1-[3-(2-N,N-di-n-propylaminoethyl)phenyl]-3-methylurea (VIIId, A=H) (HClsalt m.p. 151°-152° C.).

(B) Similarly, proceeding as in Part A above, but substitutingethylisocyanate or propylisocyanate for methyl isocyanate, the followingcompounds (VIIId, A=H) are prepared:

1-[3-(2-N,N-di-n-propylaminoethyl)phenyl]-3-ethylurea;

1-[3-(2-N,N-di-n-propylaminoethyl)phenyl]-3-propylurea.

(C) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Preparation 5(B) above for3-(2-N,N-di-n-propylaminoethyl)aniline, the following compounds (VIIId,A=H) are prepared:

1-[3-(2-N,N-ethyl-n-propylaminoethyl)phenyl]-3-methylurea;

1-[3-(2-N,N-ethyl-i-propylaminoethyl)phenyl]-3-methylurea;

1-[3-(2-N,N-ethyl-n-butylaminoethyl)phenyl]-3-methylurea;

1-[3-(2-N,N-ethyl-s-butylaminoethyl)phenyl]-3-methylurea;

1-[3-(2-N,N-ethyl-t-butylaminoethyl)phenyl]-3-methylurea;

1-[3-(2-N,N-n-propyl-n-butylaminoethyl)phenyl]-3-methylurea;

1-[3-(2-N,N-n-propyl-s-butylaminoethyl)phenyl]-3-methylurea;

1-[3-(2-N,N-n-propyl-t-butylaminoethyl)phenyl]-3-methylurea;

1-[3-(2-N,N-diisopropylaminoethyl)phenyl]-3-methylurea;

1-[3-(2-N,N-i-propyl-n-butylaminoethyl)phenyl]-3-methylurea;

1-[3-(2-N,N-i-propyl-s-butylaminoethyl)phenyl]-3-methylurea;

1-[3-(2-N,N-di-n-butylaminoethyl)phenyl]-3-methylurea;

1-(3-[2-(1-piperidyl)ethyl]phenyl)-3-methylurea;

1-(3-[2-(3,5-dimethyl-1-piperidyl)ethyl]phenyl)-3-methylurea;

1-(3-[2-(1-pyrrolidyl)ethyl]phenyl)-3-methylurea;

1-(3-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]phenyl)-3-methylurea; and

1-(3-[2-(1-azacycloheptyl)ethyl]phenyl)-3-methylurea.

(D) Similarly, proceeding as in Part A above, but substituting thecompounds made in Preparation 5(C) for3-(2-N,N-di-n-propylaminoethyl)aniline, the following compounds (VIIId,A=BzO) are prepared:

1-[2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)phenyl]-3-methylurea;

1-[2-benzyloxy-5-(2-N,N-ethyl-n-propylaminoethyl)phenyl]-3-methylurea;

1-[2-benzyloxy-5-(2-N,N-ethyl-i-propylaminoethyl)phenyl]-3-methylurea;

1-[2-benzyloxy-5-(2-N,N-ethyl-n-butylaminoethyl)phenyl]-3-methylurea;

1-[2-benzyloxy-5-(2-N,N-ethyl-s-butylaminoethyl)phenyl]-3-methylurea;

1-[2-benzyloxy-5-(2-N,N-ethyl-t-butylaminoethyl)phenyl]-3-methylurea;

1-[2-benzyloxy-5-(2-N,N-n-propyl-n-butylaminoethyl)phenyl]-3-methylurea;

1-[2-benzyloxy-5-(2-N,N-n-propyl-s-butylaminoethyl)phenyl]-3-methylurea;

1-[2-benzyloxy-5-(2-N,N-n-propyl-t-butylaminoethyl)phenyl]-3-methylurea;

1-[2-benzyloxy-5-(2-N,N-diisopropylaminoethyl)phenyl]-3-methylurea;

1-[2-benzyloxy-5-(2-N,N-i-propyl-n-butylaminoethyl)phenyl]-3-methylurea;

1-[2-benzyloxy-5-(2-N,N-i-propyl-s-butylaminoethyl)phenyl]-3-methylurea;

1-[2-benzyloxy-5-(2-N,N-di-n-butylaminoethyl)phenyl]-3-methylurea;

1-(2-benzyloxy-5-[2-(1-piperidyl)ethyl]phenyl)-3-methylurea;

1-(2-benzyloxy-5-[2-(3,5-dimethyl-1-piperidyl)ethyl]phenyl)-3-methylurea;

1-(2-benzyloxy-5-[2-(1-pyrrolidyl)ethyl]phenyl)-3-methylurea;

1-(2-benzyloxy-5-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]phenyl)-3-methylurea;and

1-(2-benzyloxy-5-[2-(1-azacycloheptyl)ethyl]phenyl)-3-methylurea.

(E) Similarly, proceeding as in Part B above, but substituting thecompounds made in Preparation 5(C) for3-(2-N,N-di-n-propylaminoethyl)aniline, the corresponding 3-ethylureaand 3-propylurea compounds (VIIId, A=BzO) are prepared.

EXAMPLE 5 (Preparation of Compounds of Formula I wherein R₃ isHydroxy)(Step 7)

(A) A solution of 3.3 g of2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene (VIIIc, A=BzO)in 150 ml of methanol was hydrogenated with 0.5 g of 10% Pd-C for 6 hr.at 2 atmospheres and 60° C. Filtration and evaporation afforded an oilwhich was dissolved in methanol and acidified with hydrogen bromide.Addition of Et₂ O precipitated the HBr salt,2-hydroxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene.HBr 148°-149° C.(I.HBr).

Similarly, proceeding as above but substituting hydrogen chloride forhydrogen bromide, the hydrochloride salts are prepared.

(B) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Example 1(C) for2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene, the followingcompounds are prepared:

2-hydroxy-5-(2-N,N-di-n-propylaminoethyl)formanilide.HBr, m.p. 116°-119°C.;

2-hydroxy-5-(2-N,N-ethyl-n-propylaminoethyl)formanilide.HBr;

2-hydroxy-5-(2-N,N-ethyl-i-propylaminoethyl)formanilide.HBr;

2-hydroxy-5-(2-N,N-ethyl-n-butylaminoethyl)formanilide.HBr;

2-hydroxy-5-(2-N,N-ethyl-s-butylaminoethyl)formanilide-HBr;

2-hydroxy-5-(2-N,N-ethyl-t-butylaminoethyl)formanilide.HBr;

2-hydroxy-5-(2-N,N-n-propyl-n-butylaminoethyl)formanilide.HBr;

2-hydroxy-5-(2-N,N-n-propyl-s-butylaminoethyl)formanilide.HBr;

2-hydroxy-5-(2-N,N-n-propyl-t-butylaminoethyl)formanilide.HBr;

2-hydroxy-5-(2-N,N-diisopropylaminoethyl)formanilide.HBr;

2-hydroxy-5-(2-N,N-i-propyl-n-butylaminoethyl)formanilide.HBr;

2-hydroxy-5-(2-N,N-i-propyl-s-butylaminoethyl)formanilide.HBr;

2-hydroxy-5-(2-N,N-di-n-butylaminoethyl)formanilide.HBr;

2-hydroxy-5-[2-(1-piperidyl)ethyl]formanilide.HBr;

2-hydroxy-5-[2-(3,5-dimethyl-1-piperidyl)ethyl]formanilide.HBr;

2-hydroxy-5-[2-(1-pyrrolidyl)ethyl]formanilide.HBr;

2-hydroxy-5-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]formanilide.HBr; and

2-hydroxy-5-[2-(1-azacycloheptyl)ethyl]formanilide.HBr.

(C) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Example 2(D) for2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene, the followingcompounds are produced:

2-hydroxy-5-(2-N,N-di-n-propylaminoethyl)acetanilide.HCl, m.p. 158°-160°C.;

2-hydroxy-5-(2-N,N-ethyl-n-propylaminoethyl)acetanilide.HBr;

2-hydroxy-5-(2-N,N-ethyl-i-propylaminoethyl)acetanilide.HBr;

2-hydroxy-5-(2-N,N-ethyl-n-butylaminoethyl)acetanilide.HBr;

2-hydroxy-5-(2-N,N-ethyl-s-butylaminoethyl)acetanilide.HBr;

2-hydroxy-5-(2-N,N-ethyl-t-butylaminoethyl)acetanilide.HBr;

2-hydroxy-5-(2-N,N-n-propyl-n-butylaminoethyl)acetanlide.HBr;

2-hydroxy-5-(2-N,N-n-propyl-s-butylaminoethyl)acetanilide.HBr;

2-hydroxy-5-(2-N,N-n-propyl-t-butylaminoethyl)acetanilide.HBr;

2-hydroxy-5-(2-N,N-diisopropylaminoethyl)acetanilide.HBr;

2-hydroxy-5-(2-N,N-i-propyl-n-butylaminoethyl)acetanilide.HBr;

2-hydroxy-5-(2-N,N-i-propyl-s-butylaminoethyl)acetanilide.HBr;

2-hydroxy-5-(2-N,N-di-n-butylaminoethyl)acetanilide.HBr;

2-hydroxy-5-[2-(1-piperidyl)ethyl]acetanilide.HBr;

2-hydroxy-5-[2-(3,5-dimethyl-1-piperidyl)ethyl]acetanilide.HBr;

2-hydroxy-5-[2-(1-pyrrolidyl)ethyl]acetanilide.HBr;

2-hydroxy-5-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]acetanilide.HBr; and

2-hydroxy-5-[2-(1-azacycloheptyl)ethyl]acetanilide.HBr.

(D) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Example 2(F) for2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene, thecorresponding propionanilide and butyranilide derivatives (VIIIb, A=H)are prepared.

(E) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Example 3(C) for2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene, the followingcompounds are prepared:

2-hydroxy-5-(2-N,N-ethyl-n-propylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-(2-N,N-ethyl-i-propylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-(2-N,N-ethyl-n-butylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-(2-N,N-ethyl-s-butylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-(2-N,N-ethyl-t-butylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-(2-N,N-n-propyl-n-butylaminoethyl)ureidonbenzene.HBr;

2-hydroxy-5-(2-N,N-n-propyl-s-butylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-(2-N,N-n-propyl-t-butylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-(2-N,N-diisopropylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-(2-N,N-i-propyl-n-butylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-(2-N,N-i-propyl-s-butylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-(2-N,N-di-n-butylaminoethyl)ureidobenzene.HBr;

2-hydroxy-5-[2-(1-piperidyl)ethyl]ureidobenzene.HBr;

2-hydroxy-5-[2-(3,5-dimethyl-1-piperidyl)ethyl]ureidobenzene.HBr;

2-hydroxy-5-[2-(1-pyrrolidyl)ethyl]ureidobenzene.HBr;

2-hydroxy-5-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]ureidobenzene.HBr; and

2-hydroxy-5-[2-(1-azacycloheptyl)ethyl]ureidobenzene.HBr.

(F) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Example 4(D) for2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene, the followingcompounds are prepared:

1-[2-hydroxy-5-(2-N,N-di-n-propylaminoethyl)phenyl]-3-methylurea.HBr;

1-[2-hydroxy-5-(2-N,N-ethyl-n-propylaminoethyl)phenyl]-3-methylurea.HBr;

1-[2-hydroxy-5-(2-N,N-ethyl-i-propylaminoethyl)phenyl]-3-methylurea.HBr;

1-[2-hydroxy-5-(2-N,N-ethyl-n-butylaminoethyl)phenyl]-3-methylurea.HBr;

1-[2-hydroxy-5-(2-N,N-ethyl-s-butylaminoethyl)phenyl]-3-methylurea.HBr;

1-[2-hydroxy-5-(2-N,N-ethyl-t-butylaminoethyl)phenyl]-3-methylurea.HBr;

1-[2-hydroxy-5-(2-N,N-n-propyl-n-butylaminoethyl)phenyl]-3-methylurea.HBr;

1-[2-hydroxy-5-(2-N,N-n-propyl-s-butylaminoethyl)phenyl]-3-methylurea.HBr;

1-[2-hydroxy-5-(2-N,N-n-propyl-t-butylaminoethyl)phenyl]-3-methylurea.HBr;

1-[2-hydroxy-5-(2-N,N-diisopropylaminoethyl)phenyl]-3-methylurea.HBr;

1-[2-hydroxy-5-(2-N,N-i-propyl-n-butylaminoethyl)phenyl]-3-methylurea.HBr;

1-[2-hydroxy-5-(2-N,N-i-propyl-s-butylaminoethyl)phenyl]-3-methylurea.HBr;

1-[2-hydroxy-5-(2-N,N-di-n-butylaminoethyl)phenyl]-3-methylurea.HBr;

1-(2-hydroxy-5-[2-(1-piperidyl)ethyl]phenyl)-3-methylurea.HBr;

1-(2-hydroxy-5-[2-(3,5-dimethyl-1-piperidyl)ethyl]phenyl-3-methylurea.HBr;

1-(2-hydroxy-5-[2-(1-pyrrolidyl)ethyl]phenyl)-3-methylurea.HBr;

1-(2-hydroxy-5-[2-(3,4-dimethyl-1-pyrrolidyl)ethyl]phenyl)-3-methylurea.HBr;and

1-(2-hydroxy-5-[2-(1-azacycloheptyl)ethyl]phenyl)-3-methylurea.HBr.

(G) Similarly, proceeding as in Part A above, but substituting thecompounds prepared in Example 4(E) for2-benzyloxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene, thecorresponding 3-ethylurea and 3-propylurea derivatives are prepared.

EXAMPLE 6 (Preparation of Salts From Free Bases)

8.0 g of 1-[3-(2-N,N-di-n-propylaminoethyl)phenyl]-3-methylurea isdissolved in methanol and acidified with methanolic HCl. The precipitateis washed with Et₂ O to give 7.0 g of the hydrochloride salt of1-[3-(2-N,N-di-n-propylaminoethyl)phenyl]-3-methylurea.

In a similar manner, all compounds of formula I in base form prepared inaccordance with the methods described above can be converted to theirpharmaceutically acceptable acid addition salts by treatment with theappropriate acid, for example, HBr, sulfuric acid, nitric acid,phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvicacid, malonic acid, succinic acid, malic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acidand the like.

EXAMPLE 7 (Preparation of Free Bases From Salts)

A solution of 3.5 g of1-[3-(2-N,N-di-n-propylaminoethyl)phenyl]-3-methylurea hydrochloridesalt in water (50 ml) is adjusted to pH 12 with NH₄ OH solution andextracted with methylene chloride. The methylene chloride is thenevaporated to afford 3 g of1-[3-(2-N,N-di-n-propylaminoethyl)phenyl]-3-methylurea as the free base.

In a similar manner, all acid addition salts of compounds of formula Iprepared in accordance with the methods described above can be convertedto their free base form.

EXAMPLE 8 (Formulations)

The following example illustrates the preparation of representativepharmaceutical formulations containing an active compound of Formula(I), e.g., 3-(2-N,N-di-n-propylaminoethyl)ureidobenzene.

    ______________________________________                                        Intraocular Solution                                                          ______________________________________                                        Active compound    0.10        g                                              Benzalkonium Chloride                                                                            0.01        g                                              EDTA               0.10        g                                              Sodium Phosphate Buffer qs                                                                       pH 7.4                                                     2% Boric acid solution qs                                                                        100         ml                                             ______________________________________                                    

The active compound is dissolved in 2% Boric acid solution, benzalkoniumchloride, sodium phosphate buffer and ethylenediaminetetraacetic acid(EDTA). The solution is then filtered through a 0.2 micron membranefilter and packaged under sterile conditions.

    ______________________________________                                        Intraocular Ointment                                                          ______________________________________                                        Active Compound    1          g                                               Benzalkonium Chloride                                                                            0.1        g                                               EDTA               1.0        g                                               White Wax          50         g                                               Petrolatum         950        g                                               ______________________________________                                    

The wax is melted over a water bath. The petrolatum is then added andheated until it liquifies. The mixture is then cooled and stirred untilit congeals. The remaining ingredients are then added as micronizedpowders and the mixture packaged under sterile conditions.

EXAMPLE 9 (Ocular Irritation Test)

Each studied compound is tested individually on a single animal byadministering, at the same time, into one eye of the animal theophthalmic solution with the test compound as an active ingredient andto the other eye only vehicle ophthalmic solution. An irritation, ifany, caused by tested compounds is compared to the non-irritating effectof the vehicle ophthalmic solution applied to the other eye. Irritationis measured by the number of blinks of each eye during the same timeperiod. Tests are performed on rats, dogs and monkeys.

Ophthalmic solutions with compounds of the invention as the activeingredient are prepared at concentrations of 0.01% to 0.5%. One drop ofthe test ophthalmic solution with active ingredient is administereddirectly into the conjuctival sack of the rat's left eye. At the sametime one drop of vehicle is administered to the conjunctival sack of therat's right eye.

Irritation of each eye is measured by counting the number of blinks forone minute after the application. The results are expressed as the meannumber of blinks±standard error per eye. The mean number ofblinks/minute is averaged for the vehicle treatment and compared to theactive compound-treated eye. Compounds may be similarly tested inmongrel dogs and rhesus monkeys.

The compounds of this invention do not elicit any irritation of theeyes, and their effects are comparable to the effect of the vehicleophthalmic solution without any active compound added.

EXAMPLE 10 (Reduction Of Intraocular Pressure)

This example illustrates the effect of compounds of the currentinvention on intraocular pressure (IOP).

Two groups of normal albino white New Zealand rabbits are used for thisstudy.

Control group: 4 animals

Experimental group: 8 animals

Experimental Schedule

At time 0, the intraocular pressure of both eyes of each animal incontrol and experimental groups is determined.

All animals receive the treatment either with saline (control group) orthe tested compound (experimental group) immediately after the 0 hourintraocular pressure reading. The control group receives 50 μl ofvehicle in each eye, while experimental animals receive 50 μl of vehiclein the left eyes and 50 μl of 1% solution of the tested compound in theright eyes.

Intraocular pressure is measured at 30 minutes, 1, 2, and 4 hours afteradministration.

Experimental Procedure

The effects of tested compounds on intraocular pressure (IOP) of rabbitsare determined using a Digilab Model 30D pneuma-tonometer. Initial IOPreadings are obtained in al animals after the administration of 50 μl of0.5% Opthaine (proparacaine hydrochloride). A group of 4 rabbits servesas control and is treated with 50 μl of saline in both eyes. Eightadditional rabbits receive 50 μl of test compound in the right eye, and50 μl of drug vehicle in the contralateral left eye. IOP readings aremade 30 minutes, 1 hours, 2 hours, and 4 hours after administration.Rabbits are observed for any signs of ocular irritation.

This procedure permits the comparison of the active compound-treatedeyes with the contralateral vehicle treated eyes, and also with salinetreated eyes. For purposes of statistical analysis comparisons are madebetween the IOP values for active compound-treated eyes, vehicle treatedcontralateral eyes and the saline treated eyes. The compounds of formulaI are active in this assay.

What is claimed is:
 1. An isotonic ophthamic composition for reducingelevated intraocular pressure, comprising a ophthalmologicallyacceptable, non-toxic carrier and a buffer and 0.001-10% wl/vol of acompound of formula I: ##STR10## or a pharmaceutically acceptable acidaddition salt thereof, whereinR₁ is alkyl of two to four carbon atoms;and R₂ is alkyl of three or four carbon atoms; or R₁ and R₂ takentogether with N form ##STR11## wherein n is 0, 1, or 2 and R₅ and R₆ areeach independently lower alkyl or hydro; R₃ is hydro or hydroxy; R₄ ishydro, lower alkyl, amino, or lower alkylamino.
 2. The composition ofclaim 1 in which the compound is3-(2-N,N-di-n-propylaminoethyl)ureidobenzene or a pharmaceuticallyacceptable salt thereof.
 3. The composition of claim 1 in which thecompound is 3-[2-(1-piperidyl)ethyl]ureidobenzene.
 4. The composition ofclaim 1 in which the compound is3-[2-(3,5-dimethyl-1-piperidyl)ethyl]ureidobenzene.
 5. The compositionof claim 1 in which the compound is2-hydroxy-5-(2-N,N-di-n-propylaminoethyl)ureidobenzene.
 6. Thecomposition of claim 1 in which the compound is2-hydroxy-5-[2-(1-piperidyl)ethyl]ureidobenzene.
 7. The composition ofclaim 1 in which the compound is2-hydroxy-5-[2-(3,5-dimethyl-1-piperidyl)ethyl]ureidobenzene.
 8. Thecomposition of claim 1 in which the compound is3-(2-N,N-n-propyl-n-butylaminoethyl)ureidobenzene.HBr.
 9. A method ofpreparing an isotonic ophthamic composition, comprising adding 0.001-10%wt/vol of a compound of formula I to an ophthalmologically acceptable,non-toxic carrier wherein the compound of Formula I is: ##STR12## or apharmaceutically acceptable acid addition salt thereof, wherein R₁ isalkyl of two to four carbon atoms; andR₂ is alkyl of three or fourcarbon atoms; or R₁ and R₂ taken together with N form ##STR13## whereinn is 0, 1, or 2 and R₅ and R₆ are each independently lower alkyl orhydro; R₃ is hydro or hydroxy; R₄ is hydro, lower alkyl, amino, or loweralkylamino adjusting the H to a range of 6.8 to 8 with an acceptablebuffer and sterilizing the composition.
 10. The method of claim 9wherein the compound of Formula I is added in an amount of 0.005-7%wt/vol.
 11. The method as claimed in claim 10, wherein the compound offormula I is3-(2-N,N-di-n-propylaminoethyl)ureidobenzene or apharmaceutically acceptable salt thereof.
 12. The method as claimed inclaim 10, wherein the compound of formula I is3-[2-(1-piperidyl)ethyl]ureidobenzene.
 13. The method as claimed inclaim 10, wherein the compound of formula I is3-[2-(3,5-dimethyl-1-piperidyl)ethyl]ureidobenzene.
 14. The method asclaimed in claim 10, wherein the compound of formula Iis2-hydroxy-5-(2-N,N-di-n-propylaminoethyl)-ureidobenzene.
 15. Themethod as claimed in claim 10, wherein the compound of formula Iis2-hydroxy-5-[2-(1-piperidyl)ethyl]ureido-benzene.
 16. The method asclaimed in claim 10, wherein the compound of formula Iis2-hydroxy-5-[2-(3,5-dimethyl-1-piperidyl)-ethyl]ureidobenzene.
 17. Themethod as claimed in claim 10, wherein the compound of formula I is3-(2-N,N-n-propyl-n-butylaminoethyl)ureidobenzene.HBr.